YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction

PLoS Biol. 2020 Dec 2;18(12):e3000941. doi: 10.1371/journal.pbio.3000941. eCollection 2020 Dec.


Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Biological Variation, Population / genetics
  • Biological Variation, Population / physiology
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / physiology
  • Female
  • Inflammation / metabolism
  • Macrophages / metabolism*
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardium / metabolism
  • Phenotype
  • Phosphoproteins / metabolism
  • Signal Transduction
  • Trans-Activators / metabolism*
  • Trans-Activators / physiology
  • Transcription Factors / metabolism
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Trans-Activators
  • Transcription Factors
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse